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Home , NDC1, Nuclear protein, Nucleoporin 88, POM121

Journal of Young Investigators RESEARCH REVIEW

The Structure and Physiology of the Complex and its Role in Expression and Human Disease

Kevin Doello1*

The Nuclear Pore Complex (NPC) is a channel that communicates and transports molecules between the cytoplasm and the . It has a complex structure composed of many structural , mainly and transporter proteins, and its biosynthesis is an extremely regulated and cell cycle phase dependent process. Moreover, in the present review, it will be shown that this structure could play a decisive role in and in the pathogenesis of several diseases. On the one hand, NPC affects gene expression by regulating epigenetic enzymes and affecting the nucleocytoplasmic balance of transcription factors and small nuclear RNAs. On the other hand, diverse studies show that NPC is involved in some diseases and pathological processes like aging, neurodegenerative diseases and extrapyramidal syndromes, cancer, cardiovascular diseases, infectious diseases and genetic syndromes. In conclusion, NPC might be an important element in the control of gene transcription and cell phenotype, and perhaps, it will become a future pharmacologic target for several diseases in which it is involved in. INTRODUCTION The Nuclear Pore Complex (NPC) is a cellular component that is cytoplasmic filaments, and nuclear ring. They are all made by located within the . It is a protein channel that approximately 30 different proteins called nucleoporins allows macromolecules to cross from the cytoplasm to the (D’Angelo and Hetzer 2008). nucleoplasm and vice versa. This establishes an important Nuclear basket is composed of a ring of nucleoporins physiological process known as nucleocytoplasmic transport (Nup153 and Nup50) which bind filaments of Tpr protein, (Jamali et al. 2011). NPCs are not only involved in transport but making up a structure with a basket shape (Brohawn et al. 2009; also have an important relationship with epigenetic enzymes and Hoelz et al. 2011). Cytoplasmic filaments are made up by the transcription factors, which are both proteins that participate in nucleoporins Nup88, Nup214 and Nup358 (Brohawn et al. 2009; gene expression (Van de Vosse et al. 2011). Moreover, it has Hoelz et al. 2011). Finally, the nuclear ring has four parts, been demonstrated that the NPC is linked to many diseases such namely, the membrane ring, the spoke ring, the inner ring or as aging, neurodegenerative diseases and extrapyramidal nuclear ring, and the outer ring or cytoplasmic ring. The syndromes, cancer, cardiovascular diseases (arrhythmias and membrane ring anchors the NPC to the nuclear envelope and sudden death), infectious diseases and genetic syndromes. For comprises nucleoporins gp210, Ndc1 and Pom121. The spoke example, in cancer or genetic syndromes, mutations exist in the ring is located centrally in respect to the membrane ring and is proteins that form the NPC (Capelson and Hetzer 2009). The built by nucleoporins Nup53, Nup54, Nup58, Nup62 Nup93, objectives of this review are to revise the structure and Nup98, Nup155, Nup188 and Nup205 (Brohawn et al. 2009; physiology of the NPC and investigate its role in gene expression Hoelz et al. 2011). Finally, the outer and the inner rings are and diseases in order to clearly understand the possible role of composed of nucleoporins Nup37, Nup43, Nup85, Nup96, the NPC as a gene expression regulator and a future therapeutic Nup107, Nup133, Nup160, Sec13 and Seh1 (Alber et al. 2007; target. Beck et al. 2007; Brohawn et al. 2009; Cronshaw et al. 2002; Hoelz et al. 2011; Lim et al. 2008; Stoffler et al. 2003). Another Structure of the nuclear pore complex protein called or Adracalin (Cronshaw and Matunis 2003) The NPC is an octagonal protein channel (Fabergé 1973) that is is located at the NPC as well and binds to a named between 40 and 90 nm in diameter (Webster et al. 2009) and 200 Ndc1 (Kind et al. 2009; Yamazumi et al. 2009) (Figure 1). nm in depth (Gall 1967). There are approximately 2000 NPCs in The nucleoporins that form the NPC can be classified a cell. Nevertheless, this number can vary depending on the cell into three groups: transmembrane nucleoporins (approximately type studied, the phase of the cell cycle and external aggressions 10%); structural nucleoporins (50%); and FG-nucleoporins (40% (Maeshima et al. 2011; Maul et al. 1980). of the total population) (Rout and Wente 1994). There are three structures within a NPC: nuclear basket, The deepest nucleoporins in the NPC project some of their peptide fragments into the pore hole. These peptide 1 School of Medicine, University of Granada, 18071 Granada, sequences are natively unfolded and hence are polypeptides Spain without a secondary structure folding. They make up a peptide web within the pore complex hole. In this web there are *To whom Correspondence should be nucleoporins containing GLFG (glycine-leucine-phenylalanine- addressed: [email protected] glycine repeats), FXFG (phenylalanine-x-phenylalanine-glycine repeats) and FG (the most common type) (phenylalanine-glycine

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repeats). These FGs are extremely important for the NPC’s Function of the nuclear pore complex involvement in the nucleocytoplasmic transport of NPC is responsible for the exchange of macromolecules and macromolecules, as FGs function as the anchoring points for the other substances between the nucleus and the cytoplasm cargo, indicate the direction of transport and adapt to appropriate (nucleocytoplasmic transport). There are two forms of transport. pore size (Denning et al. 2003; Terry and Wente 2009; Yang 1) simple diffusion, which occurs in molecules smaller than 40 2011). kDa (e.g. water, ions and metabolites) (Keminer and Peters 1999) The NPC is tightly bound to the nuclear membrane and and 2) nuclear translocation, for macromolecules like mRNA, the by protein Pom121 and another NPC proteins, snRNA, tRNA, microRNA, transcription factors, histones, respectively (Hawryluk – Gara et al. 2005; Mitchell et al. 2010). enzymes and even viral proteins and nucleic acids (Ribbeck and The protein Pom121 comprises membrane ring in the NPC Görlich 2001). (Mitchell et al. 2010) and anchors NPC to nuclear membrane, Nuclear translocation can happen in two directions: while other NPC proteins are involved in the anchorage with nuclear import, in which molecules go into the nucleus, and nuclear export, a phenomenon where molecules go out to the cytoplasm. Both of them are extremely regulated processes and require transporter proteins (Jamali et al. 2011).

Transport proteins involved in nucleocytoplasmic transport Transporter proteins can be classified into two groups: energetic molecules and anchoring molecules. Both of them are located in the NPC and are fundamental for nucleocytoplasmic transport (Marelli et al. 2001). Ran is a protein, from the family of Ras, which supplies the energy needed for the nucleocytoplasmic transport. It binds GTP or GDP, so it carries phosphate groups between the nucleoplasm and the cytoplasm (Sekiguchi et al. 2000). Anchoring transport proteins are called kariopherins. There are two kinds of kariopherins, namely exportins and importins (Gorlich and Laskey 1995; Marelli et al. 2001). Exportins, a protein group with seven elements, transport cargo from nucleus to cytoplasm (nuclear export) after recognizing them by a peptide sequence called nuclear export signal (NES) which is rich in leucine (Kutay and Güttinger 2005). On the other Figure 1. The nuclear pore complex (NPC). This image shows the main hand, importins transport molecules from the cytoplasm to the parts in which the NPC is divided and the specific proteins that compound nucleus (nuclear import) when a sequence known as nuclear them. Nuclear basket (in orange) is composed of Nup153 and Nup50 which bind filaments of Tpr protein. Cytoplasmic filaments (in purple) are localization signal (NLS) is located in the cargo (Kalderon et al. made up by the nucleoporins Nup88, Nup214 and Nup358. The nuclear 1984). ring has four parts, namely, the membrane ring (in brown), the spoke ring Importins are more complex than exportins because (in red and grey), the inner ring or nuclear ring and the outer ring or they are composed of two subunits called importin A and cytoplasmic ring (both in green). The membrane ring anchors the ring importin B that work together, but in some cases they can also complex to the nuclear envelope and comprises nucleoporins gp210, Ndc1 work separately. There are many forms of importin A and B, and and Pom121. The spoke ring comprises the nucleoporins Nup53, Nup54, consequently, lots of different combinations exist as well Nup58, Nup62 Nup93, Nup155, Nup188 and Nup205. The outer and the (Gorlich et al. 1995) inner rings are composed of nucleoporins Nup37, Nup43, Nup85, Nup96, Nup107, Nup133, Nup160, Sec13 and Seh1. Other important proteins are Nuclear Import also show in the picture. Nuclear import starts with a cytoplasmic protein that contains a NLS that is recognized by importin A, which then subsequently binds to Importin B. Although, this is the paradigm, many NLS nuclear lamina (A-lamina and B-lamina proteins) Lamina are recognized by importins that are not made up by two determines the location of NPC, because NPCs are more frequent subunits. The Cargo NLS – Importin A – Importin B complex in places of the nuclear envelope with B – lamina and less interacts with the elements of the NPC, more exactly with the FG common in the regions with A – lamina. Nup53, Nup153 and - Nups, binding to FG, GLFG or FXFG nucleoporins Pom121 bind to B – lamina, while Nup 88 binds to A – lamina temporarily. Not all FG - Nups have the same affinity to the (Hawryluk – Gara et al. 2005; Hawryluk – Gara et al. 2008; importin (especially importin B), existing FG - Nups called Lussi et al. 2011; Mitchell et al. 2010; Schwarz – Herion et al. clusters with more binding power (Bayliss et al. 2000; Ribbeck 2007; Smythe et al. 2000). and Görlich 2002). At the nuclear basket, the transport complex interacts with the nucleoporin Nup50. Nup50 binds to Nup135

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and has three domains, namely a C - terminal extreme, a FG Finally, new RanGTP is formed from RanGDP. This cycle domain and a N - terminal extreme. Importin B binds to the FG happens in the nucleus and the cytoplasm, creating a Ran domain of Nup50 and separates from Cargo NLS – Importin A gradient that occurs from nucleus to cytoplasm because RanGTP complex. Then Importin A binds to the N - terminal extreme of is in a higher concentration in nucleus than in the cytoplasm. Nup50, releasing the cargo (Stewart 2007). It is fundamental for This gradient aids to transport molecules. Nup50 to be phosphorylated at serine-221 and serine-315 in Ran cycle starts with a RanGTP that binds to a Cargo - order to function properly (Kosako et al. 2010). NES – Exportin complex inside the nucleus. As RanGTP is in a Parallel to this process, RanGDP, the energy carrier in higher concentration in the nucleus than in the cytoplasm, the nucleocytoplasmic transport, comes back to the nucleus. complex is exported outside the nucleus. In the cytoplasm, Ran is RanGDP is carried by the protein NTF2, a dedicated nuclear- separated from the complex and binds to RanBP1 and RanBP2. import factor for Ran (Stewart 2000). An enzyme called GAP degrades the GTP to GDP. RanGDP is Importin A and importin B are back to the cytoplasm returned back to the nucleus by NFT2. Both separate with the with different mechanisms of transport. Importin A is transported involvement of Nup50, because RanGDP binds to the C – by cellular apoptosis susceptibility (CAS) and RanGTP, while terminal extreme of Nup50, also called the Ran binding domain importin B is only carried by RanGTP (Kutay et al. 1997; Ström (RBD) (Sazer and Dasso 2000; Yoneda et al. 1999). and Weis 2001). In the nucleus, an enzyme called GEF (guanine nucleotide exchange factor) transforms GDP into GTP, synthesizing new RanGTP, so that a new cycle begins (Sazer and Dasso 2000; Yoneda et al. 1999) (Figure 2).

Biophysics of nucleocytoplasmic transport In order to explain the function of FG – Nups there are some discrepancy among the authors. In fact, there are four models in order to explain it called the “virtual gating/polymer brush model”, the “reduction of dimensionality model”, the “selective phase/hydrogel model” and the “forest model”. The first one proposes that non - interacting FG – Nups create an entropic barrier that can only be crossed when the cargo attaches to them. The second model suggests that FG – Nups Figure 2. Nuclear import, export and Ran cycle. This picture shows these processes and the configure a small hole that permits the elements that are involved in them. The legend identify each element of the nucleocytoplasmic passive diffusion of small molecules and transport in the picture. All of the proteins and the process shown are fully explained in the the transport of large ones by translocation main text. . The third one hypothesizes that FG – Nups have big interactions which Nuclear export contribute to the creation of a hydrogel inside the pore. When Nuclear export begins with a that contains a NES. transport complexes bind to the FG – Nups, the hydrogel This peptide sequence is recognized by exportins which also bind disappears and transport can occur. Finally, the fourth model to RanGTP. This Cargo NES – Exportin – RanGTP complex proposes that there are two fragments in FG – Nups, namely, the travels from the nucleus to the cytoplasm. The exportin interacts globular domains, that create a central channel for the transport with the nucleoporins (FG – Nups) on the same way as of small molecules, and the extended coils, which configure a importins. In the cytoplasm, RanGTP binds to RanBP1 and peripheral zone for the transport of larger molecules (Yang et al. RanBP2, and releases the Cargo – Exportin complex, which 2011). subsequently disassembles (Goldberg 2004). In any case, Moussavi et al. (2011) demonstrated that this transport is not lineal but follows a Brownian movement, Ran cycle employing between 5 and 10 ms. Nucleocytoplasmic transport would not proceed without Ran, a protein which provides the energy needed in this process. It is a Transport of messenger RNA from the nucleus cycle that begins with a Ran binding to a GTP molecule. Messenger RNA (mRNA) is exported by a complex process that Afterwards, this GTP is hydrolyzed and appears RanGDP. varies with respect to the standard explanation. First of all, DNA

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is transcribed by RNA polymerase II. At the same time, SAGA, a (Tanenbaum et al. 2011). protein associated to the gene in transcription, binds the DNA In addition, NPC mediates the import of the steroids chain to the NPC so that the transcription process happens near hormones and its receptor, allowing them to carry out their the NPC. SAGA specifically attaches to a complex called TREX function as a transcription factor. This complex process starts – 2 which binds to the NPC. RNA polymerase II also binds to a with the steroid receptor (SR) which is anchored to a complex of complex called THO/TREX that joins with TREX – 2. The transporter proteins that is made up of hsp90, hsp70, hsp40, Hop synthesized mRNA joins with the protein UAP56. Afterwards, and p23. Afterwards, the steroid hormone binds to the receptor. during splicing mRNA also binds with Aly protein. Aly interacts Subsequently, Hop is replaced for TPR protein. The complex is with the complex TAP/NXT1 which transports the mRNA along then carried to the NPC by dynein and NPC transports it to the the nuclear pore hole. During this transit is very important the nucleoplasm. There, the hormone – receptor complex is released interaction of mRNA with two nucleoporins, Nup98 and and acts as a transcription factor (Galigniana et al. 2010). Nup153. The energy required for this process is provided by the Finally, it is important to mention that some nuclear protein Dbp5. This protein is a part of the DEAD – box and basket proteins like Tpr develop specifics functions. For anchors to another protein called Gle1, which is located at the example, this protein regulates Mad 1 and Mad 2, two proteins cytoplasmic filaments. But, the most important thing is that this which are very important in the cell cycle (metaphase) and protein needs inositol hexa – phosphate (IP6) in order to make anchors some activated and silenced telomeres (Lee et al. the export of mRNA possible (Hocine et al. 2010; Ling et al. 2010). 2010; Stewart 2010) (Figure 3). Biosynthesis of the nuclear pore complex Other roles of the nuclear pore complex There are three occasions within the cell cycle in which NPCs NPC is not only involved in nucleocytoplasmic transport, but are synthesized, including interphase, G2 phase, and after also plays a key role in other cellular functions. anaphase when nuclear envelope begins to configure (Fernández NPC serves as an anchoring place for the enzymes – Martínez et al. 2009; Maeshima et al. 2011). kinesin - 1 and dynein. Kinesin – 1 binds to Ran BP2 and NPC biogenesis starts when Pom121 migrates through microtubules and carries the nucleus to a cell pole. Dynein binds the nuclear envelope from the outer membrane to the inner to Ran BP2 and BICD2, an adaptor protein of the SUN – KASH membrane. Pom121 is a transmembrane protein which possesses family, and transports the nucleus to a central position a luminal domain (cadherin - like domain) and a nucleoplasmic domain. This last, known as LBR domain, recognizes regions in the nuclear lamina with lamina B. So, the biosynthesis of new NPC occurs mainly in rich lamina B regions. The places where Pom121 concentrates are also determined by Heh1p and Heh2p, two proteins from the LEM - domain family (a family of proteins that are located within the inner nuclear membrane and nucleus). These proteins are located in determined regions of the nuclear envelope and bind Pom121 by the cadherin like luminal domain. SUN1 protein is also implicated in Pom121 distribution along the nuclear envelope. Pom121 activates alcalin - phosphatase 5 and the Nup133 enzyme. This nucleoporin activates Nup155 and Nup35, which fuse the two nuclear layers (the inner and the outer layer of the nuclear envelope). In these zones Pom121 and ELYS recruit the complex Nup107 – 160 (Nup84) which attracts other nucleoporins, ending the construction of the NPC.

Regulation of the expression of the NPC components NPC expression differs depending on the cell type. Cells that are able to proliferate have a higher number of NPC and increased NPC turnover. Moreover, the phase of the cell cycle has an important determining role in NPC expression. For example, in G2 cell cycle phase, NPC number increases (Maeshima et al. Figure 3. mRNA export. This image explains the process of mRNA 2011). export, since it is transcribed until it is taken out from the nucleus. Moreover, some genes like HEH1 and HEH2 determine RNAm transcription, as recent investigations demonstrate, starts near the level of expression of the nucleoporins. HEH1 affects the NPC because RNA polymerase II (in yellow) is anchored to NPC by a expression of Nup153, Nup50, Pom121, Ndc1 and RTN1 complex comprised of THO/TREX (in green) and TREX-2 (in blue). (reticulon 1). HEH2 determines the level of expression of Then, the transcribed mRNA binds to other proteins (TAP/NXT1, Nup160, Nup107, Nup155 and Nup188. Some nucleoporins, Dbp5, Aly) that transport mRNA to the cytoplasm via NPC. All of namely Nup35, Nup133, Nup59, gp210 and APQ12, interact the proteins and the process shown are fully explained in the main text. 90 JYI | June 2013 | Vol. 25 Issue 6  2013 Journal of Young Investigators Journal of Young Investigators RESEARCH REVIEW

simultaneously with HEH1 and HEH2 (Yewdell et al. 2011). balance of NFAT, cyclin B and AP – 1 (Turner and Sullivan . However, not only does the genetic environment 2008). Nup88 determines the quantity of NFkB that accumulates determines NPC expression, but the tissue environment, in the nucleoplasm (Takahashi et al. 2008). Nup88 and Nup214 particularly Ras signaling pathway, PIK3 signaling pathway and are extremely important for keeping the transcription factor AMP kinase, does as well. Ras signaling pathway is responsible Cactus – Dorsal/Dif in nucleus, which is the responsible for for cell proliferation and the PIK3 signaling pathway is transcribing genes related to innate immune response (Wiermer responsible for cell growing. So, both cell proliferation and cell et al. 2010). IPO12 imports splicing factors like SFRS1 and growing are processes that regulate NPC expression. In the Ras SFRS2 (Kataoka et al. 1999). signaling pathway, mitogens activate Ras and Raf, Mek, Erk and NPC complex also controls the import of snRNAs. Rsk proteins. Erk phosphorylates Nup50 (its phosphorylation These molecules act as regulators of transcription factors, diminishes the binding with importin B), Nup153 and Nup214, participate in mRNA splicing and maintaining the telomeres while Rsk phosphorylates RanBP3, which determines the Ran – (Neuman de Vegvar and Dahlberg 1990). GTP gradient (Kodiha et al. 2010; Kosako and Imamoto 2010; Maeshima et al. 2011). In the PIK3 signaling pathway, growing Role in pathology factors stimulates PIK3 which phosphorylates and NPCs are altered in many diseases such as cancer, GlcNAcetylates Nup50, Nup62, Nup88, Nup153, Nup214, CAS, neurodegeneration, viral infections and cardiovascular Importin – A and RanBP3. Moreover, AMP has an important pathologies. role of phosphorylating and acetylating Importin A (Kodiha et al. 2010). NPC and its role in cancer Finally, oxidative stress also affects NPC, particularly, NPC number has been demonstrated to be increased in cancer nucleoporins, importins, exportins and Ran nucleocytoplasmic (Maul et al. 1980). Moreover, some mutations of NPC proteins localization and function. Oxidative stress also has a very are characteristic in some types of cancer. For example, Nup88 is important relationship with importin A, Importin B1 and Nup153 over expressed in tumors of advanced state. Some authors even (Kodiha et al. 2004, 2008). Termical and hiperosmotic shocks expose that Nup88 has an important role in their invasive also affect Ran gradient (Kelley and Paschal 2007; Kodiha et al. character. It is found to be over expressed in breast, colon and 2004). Moreover, ceramide provokes the mislocalization of CAS hepatic cancer (Agudo et al. 2004; Zhang et al. 2004). Another and Importin A (Faustino et al. 2008). Furthermore, aging mutation that involves the translocation of Nup98 with HOXA9 deregulates Importin A, CAS and RanBP1 (Pujol et al. 2002). occurs in leukemia. This mutation determines the expression of Finally, some immune molecules like interferon gamma oncogenes and stops the differentiation of hematopoietic cells upregulate the expression of Nup98 and Nup96 (Enniga et al. (Kasper et al. 1999). Another protein called Nup214 translocates 2002). with Dek and Set. This translocation is also involved in leukemia

Role in gene expression As recent investigations show, NPC could be an important cellular element in the regulation of gene expression. According to the evidences, this mechanism could take place in two ways, either by regulating epigenetic enzymes or affecting the nucleocytoplasmic balance of transcription factors and small nuclear RNAs (snRNAs) (Griffis et al. 2004; Kasper et al. 1999; Kataoka et al. 1999; Mingot et al. 2001; Neuman de Vegvar and Dahlberg 1990; Petit et al. 2008; Ploski et al. 2004; Takahashi et al. 2008; Turner and Sullivan 2008; Wang et al. 2007; Wiermer et al. 2010). Gene expression is determined by epigenetic regulation. NPC interacts with CBP/p300, a histone acetil – transferase, and with NSD1, a histone metil transferase, which affect the transcription either positively or negatively (Kasper et al. 1999; Petit et al. 2008; Wang et al. 2007). NPC has also an important role as a transcription factor and involves nucleoporins Nup1, Nup2, Nup60, Nup88, Nup98, Nup153 and Nup157 (Griffis et al. 2004). Moreover, NPC regulates gene expression in other way: by determining the proportion of concrete transcription factors in the nucleus and cytoplasm. IPO13 imports the transcription Figure 4. Diseases and nuclear pore complex. This picture indicates factor Pax6 and releases elF1A (Mingot et al. 2001; Ploski et al. some pathological processes demonstrated to have NPC involvement. 2004). XPO1 or CRM1 determines the nucleocytoplasmic

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(Ageberg et al. 2008; Boer et al. 1998). Tpr, a nuclear basket infantile bilateral striatal necrosis. This syndrome is due to a protein, translocates with Met (tirosin kinase of HGF) and this is mutation in the nucleoporin, Nup62 (Figure 4). linked with gastric cancer (Soman et al. 1991). Tpr can also As it has been seen, a lot of pathologies have a translocate with Ntrk1 (NGF tirosin kinase) which is related to relationship with the NPC. Therefore, the structures of the NPC thyroid cancer (Greco et al. 1992; Greco et al. 1997). Ran is also that are affected or involved in these pathologies could be over expressed in cancer, making nuclear protein synthesis faster therapeutic targets. In fact, Chahine and Pierce (2009) compile (Sanderson and Clarke 2003). Finally, it has recently been some studies in which pharmacologic targeting at the discovered that mitotic spindle formation in cancer cells depends mechanisms of nuclear import have satisfactory laboratory on a Ran-Survivin complex, something not present in normal results for the treatment of several diseases. cells. The alteration of this complex by inhibition provokes aberrant mitosis and apoptosis of cancer cells (Xia et al. 2008). Conclusion The NPC is a cellular structure located in the nuclear envelope, NPC and its role in aging which permits the transport of macromolecules between the NPC and aging could be linked. Cells without capacity of nucleus and the cytoplasm. However, recent studies have proliferation do not turnover their NPC. So, aging process would demonstrated that its function is more complex, having an provoke NPC degradation and poor cell and genetic functioning important role in gene expression and disease. as time goes by (Fernández – Martínez and Rout 2009) . On the one hand, it has been exposed the role of NPC in the regulation of epigenetic enzymes. So that, NPC might be one NPC and its role in neurodegenerative diseases of the cell elements responsible for maintaining cellular NPCs are thought to be involved in neuro degenerative diseases epigenetic memory and cell phenotype. On the other hand, as it because neurons do not proliferate and NPCs are not renewed has been explained, concrete NPC proteins play an important role causing NPCs to degenerate and neurons to die. High levels of in the nucleocytoplasmic transport of snRNAs and many ionic calcium are also involved in neural degeneration which is transcriptions factors. Therefore, the quantity of a determined thought to be due to calcium-dependent pore degeneration (Bano transcription factor that is located in nucleus might depend on the et al. 2010a, 2010b). proportion of the concrete nucleoporins, importins and exportins that compounds the NPC of a cell. Transcriptions factors and NPC and its role in viral infections snRNAs control gene expression, so NPC might also control NPC also plays an important role in viral infections because the gene expression at this level. nucleocytoplasmic transport of viral molecules depends on NPC. Futhermore, many diseases and pathological processes Moreover, some viruses disrupt NPC normal function when they such as cancer, aging, neurodegenerative diseases and viral are within the host cell. For example, HIV integrase has a infections have demonstrated to have a relationship with NPC. specific NLS and is imported by TNPO3 (an importin) (Ocwieja As a consequence, NPC could become future therapeutic target et al. 2011; Woodward and Chow 2010). Another example is to treat these processes. poliomyelitis virus which hydrolyzes Nup153 and impedes normal nucleocytoplasmic transport (Gustin and Sarnow 2001). ACKNOWLEDGEMENT Sincere thanks to Oscar Doello for his technical aid in the design NPC and its role in other diseases of the images shown in this manuscript. Many mutations in genes of nucleoporins provoke severe diseases. For example, a mutation in Nup155 is believed to produce atrial fibrillation and sudden death (Chen et al. 2008). REFERENCES Moreover, mutations in Nup133 are related to poor embryonic neural development (Lupu et al. 2008). ELYS (another NPC Ageberg, M et al. (2008) Identification of a novel and myeloid protein) mutation inhibits normal development in retina and specific role of the leukemia – associated fusion protein intestine (de Jong Curtain et al. 2009). Furthermore, some DEK – NUP214 leading to increased protein synthesis. authors link primary biliary cirrhosis with damage in Nup62 Genes Cancer 47(4): 276-87. (Tartakovsky and Worman 1995). Agudo, D et al. 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